The field of the present invention is the treatment of intracranial aneurysms using focused ionizing radiation. An intracranial aneurysm (brain aneurysm) is a disorder in which weakness in the wall of a cerebral artery causes a localized dilation or ballooning of the blood vessel. Intracranial aneurysms are classified into several basic types—the rounded saccular aneurysms; the spindle-shaped fusiform aneurysms; and Charcot-Bouchard aneurysms (also known as microaneurysms or miliary aneurysms). Charcot-Bouchard aneurysms are associated with hypertension and occur in blood vessels less than 300 microns in diameter, particularly in the lenticulostriate vessels of the basal ganglia. Blister-like aneurysms, traumatic and dissecting aneurysms, and infectious aneurysms have also been described. For each of these aneurysm types, all layers of the blood vessel wall are dilated or ballooned, such that a portion of the blood vessel lumen itself is enlarged. In contrast to those true aneurysms, the wall of an intracranial pseudoaneurysm (false aneurysm) is composed mainly of blood clot and fibrous tissue that does not distend all layers of the blood vessel, because it forms only between internal layers of a vessel wall.
The present invention is concerned in particular with the treatment of saccular aneurysms, which are rounded, berrylike outpouchings that arise primarily from arterial bifurcation points. In contrast to fusiform aneurysms that are generally associated with atherosclerosis and that are found in portions of arteries in locations upstream of major bifurcations or branch points, saccular aneurysms are found at the apex of bifurcations at the origin of small arteries branching from large ones, and on the sidewall of arteries with sharp curvatures. Saccular aneurysms account for approximately 90% of intracranial aneurysms and mainly appear in the intracranial arteries about and near the Circle of Willis, which is a circulatory anastomosis that supplies blood to the brain. The Circle of Willis comprises the anterior communicating artery and the following left and right arteries: anterior cerebral artery, internal carotid artery, posterior cerebral artery and posterior communicating artery. Over 85% of the brain aneurysms form in the anterior part of the circle, which is supplied by the two carotid arteries.
When an aneurysm ruptures, blood flows from the aneurysm lumen into the subarachnoid space, which is the opening between the arachnoid membrane and the pia mater surrounding the brain. The result is a form of stroke known as a subarachnoid hemorrhage. Symptoms of a subarachnoid hemorrhage include a severe headache with a rapid onset (“thunderclap headache”), vomiting, confusion or a lowered level of consciousness, and sometimes seizures. The association of meningeal signs should also raise suspicion of a subarachnoid hemorrhage [VAN GUN J, Kerr R S, Rinkel G J. Subarachnoid haemorrhage. Lancet 369 (9558, 2007): 306-318]. Some ruptured aneurysms are also accompanied by a hematoma, i.e., a localized swelling that is filled with leaked blood that is usually clotted or partially clotted [Khalid M. ABBED K M and Christopher S Ogilvy. Intracerebral hematoma from aneurysm rupture. Neurosurg Focus. 15(4, Oct. 15, 2003): Article 4, pp. 1-4]. Hematomas can exert a clinically significant mass effect, where “mass effect” refers to the distortion, displacement and/or compression of areas of brain tissue that surround space that is newly-occupied by the leaked blood [Allyson R. ZAZULIA, MD; Michael N. Diringer, MD; Colin P. Derdeyn, MD; William J. Powers, MD. Progression of Mass Effect After Intracerebral Hemorrhage. Stroke 30 (1999):1167-1173; Beth RUSH. Mass Effect. In: Kreutzer J. S., DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, N.Y. (2011), page 112]. Following the rupture of a cerebral aneurysm, a perianeurysmal hematoma can exert a mass effect on the ruptured aneurysm itself, by pressing on the aneurysm to change its shape and by displacing the aneurysm from its original location, an example of which is the observed displacement of an aneurysm by 8.9 mm after rupture, due to the formation of a perianeurysmal hematoma having dimensions 28×22×35 mm [CORNELISSEN B M, Schneiders J J, Potters W V, van den Berg R, Velthuis B K, Rinkel G J, Slump C H, Van Bavel E, Majoie C B, Marquering H A. Hemodynamic Differences in Intracranial Aneurysms before and after Rupture. AJNR Am J Neuroradiol. 36(10, October 2015):1927-1933, on p. 1929; SCHNEIDERS J J, Marquering H A, van den Berg R, Van Bavel E, Velthuis B, Rinkel G J, Majoie C B. Rupture-associated changes of cerebral aneurysm geometry: high-resolution 3D imaging before and after rupture. AJNR Am J Neuroradiol. 35(7, July 2014):1358-1362, see its FIG. 3].
Most aneurysms do not cause symptoms until they rupture. When they do rupture, they are associated with significant morbidity and mortality. The most common presentation of an intracranial aneurysm is, in fact, a subarachnoid hemorrhage. In North America, 80-90% of non-traumatic subarachnoid hemorrhages are caused by rupture of an intracranial aneurysm. Of patients with a subarachnoid hemorrhage, 10-15% promptly die, 50% die within a month, and 50% of survivors have neurological deficits. Ruptured aneurysms have their highest rebleeding rate within the first day. If untreated, at least 50% rebleed during the 6 months after the initial hemorrhage. Immediate care along with aggressive anti-ischemic treatment, such as antivasospastic drugs, intravascular volume expansion and transcranial doppler monitoring, are often crucial to achieving the best possible outcome.
An aneurysm may be detected incidentally during the diagnosis or treatment of some other brain disorder. But most times the patient's aneurysm is latent until it causes symptoms. Therefore, for some patients it may be advisable to screen for aneurysms. The patients at highest risk are those for whom aneurysms run in their families, patients exhibiting multiple- or previously ruptured aneurysms, and patients exhibiting certain conditions such as systemic lupus erythematosus and genetic disorders such as autosomal dominant polycystic kidney disease [Hae Woong JEONG, Jung Hwa Seo, Sung Tae Kim, Cheol Kyu Jung, and Sang-il Suh. Clinical practice guideline for the management of intracranial aneurysms. Neurointervention 9(2014):63-71].
According to angiography and autopsy studies, the prevalence of intracranial aneurysms ranges from 0.5%-6% in adults. The risk of aneurysm rupture is difficult to determine precisely, but is estimated to be cumulatively 1-2% per year, for asymptomatic lesions that have not yet ruptured. With a combined operative mortality rate and major morbidity risk of about 3.5% for aneurysm surgery performed by a skilled physician, imprecise conclusions are that any patient with a life expectancy of more than 3 years would benefit from surgical obliteration of an unruptured asymptomatic aneurysm. Ruptured aneurysms that are not treated have a very high risk of rebleeding after the initial hemorrhage has occurred. The risk is estimated at 20-50% in the first 2 weeks, and such rebleeding carries a mortality rate of nearly 85%.
Depending on the aneurysm's location, more precise individualized treatment algorithms indicate that unruptured aneurysms should be treated surgically if they exceed a certain diameter and/or expansion growth rate and/or aspect ratio (aneurysm depth to aneurysm neck) [NADER-SEPAHI A, Casimiro M, Sen J, Kitchen N D. Is aspect ratio a reliable predictor for intracranial aneurysm rupture? Neurosurgery 54 (6, 2004): 1343-1348; UJIIE H, Tachibana H, Hiramatsu O, Hazel A L, Matsumoto T, et al. Effects of size and shape (aspect ratio) on the hemodynamics of saccular aneurysms: a possible index for surgical treatment of intracranial aneurysms. Neurosurgery 45 (1, 1999): 119-130]. This leaves physicians with the therapeutic dilemma of either subjecting patients with borderline smaller aneurysms to a complex surgery having high morbidity and complications, or simply surveilling an aneurysm having a risk of rupture that might be acceptable. It is worth noting that 13% of ruptured aneurysms are less than 5 mm in diameter, so aneurysm size alone should not be the only consideration [KASSELL N F, Torner J C. Size of intracranial aneurysms. Neurosurgery 12(1983):291-297].
Accordingly, grading scales have been developed to help decide objectively the likelihood that a patient with an aneurysm will not experience a rupture, or to suggest the most appropriate time to perform surgery if a rupture has already occurred. The most commonly used grading scales are the Hunt and Hess Scale, the Fisher Scale, the Glasgow Coma Score, and the World Federation of Neurological Surgeons (WFNS) Scale. But no less than 40 other scales have been proposed. The Hunt and Hess Scale and the modified Fisher Scale both assign grade 0 to an unruptured aneurysm and therefore do not contemplate heterogeneous risks among unruptured aneurysms. In contrast, some scales are designed specifically for unruptured aneurysms [HUNT W E, Hess R M. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28(1968):14-20; FRONTERA J A, Claassen J, Schmidt J M, Wartenberg K E, Temes R, Connolly E S Jr, MacDonald R L, Mayer S A. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery 59 (1, 2006): 21-27; OGILVY, Christopher S. and Carter, Bob S. A Proposed Comprehensive Grading System to Predict Outcome for Surgical Management of Intracranial Aneurysms. Neurosurgery 42 (5, 1998): 959-968; KHANNA R K, Malik G M, Qureshi N: Predicting outcome following surgical treatment of unruptured intracranial aneurysms: A proposed grading system. J Neurosurg 84(1996):49-54].
Instead of, or in addition to, the use of grading scores, other authorities provide somewhat more subjective advice about the treatment of unruptured and ruptured aneurysms, which is intended to shape the judgment of the physician who will either treat or surveil the aneurysm [SOLOMON R A, Fink M E, Pile-Spellman J: Surgical management of unruptured intracranial aneurysms. J Neurosurg 80(1994):440-446; SONOBE M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 41(2010):1969-1977].
Surgical ligation and clipping has been the standard treatment of intracranial aneurysms for decades. Microsurgical techniques have evolved over the years, and a variety of surgical approaches and metal aneurysm clips have been developed. For patients having complex aneurysms, bypass surgery and vascular reconstruction may be needed. Surgical treatment has proven to be highly effective, with reported rates of complete occlusion of unruptured aneurysms of approximately 90-95%, with an extremely low rate of subsequent subarachnoid hemorrhage. Surgical repair of aneurysms in the posterior intracranial circulation, however, is extremely difficult due to technical access issues [POLEVAYA N V, Kalani M Y, Steinberg G K, Tse V C. The transition from hunterian ligation to intracranial aneurysm clips: a historical perspective. Neurosurg Focus 20 (6, 2006):E3, pp. 1-7; Nicola ACCIARRI, Giovanni Toniato, Andreas Raabe, and Giuseppe Lanzion. Clipping techniques in cerebral aneurysm surgery. Journal of Neurological Sciences 60 (1, 2016): 83-94; Harley Brito D A SILVA, Mario Messina-Lopez, and Laligam N. Sekhar. Bypasses and Reconstruction for Complex Brain Aneurysms. Methodist Debakey Cardiovasc J. 10 (4, 2014): 224-233].
In 1991, Guido Guglielmi described a technique of occluding aneurysms with an endovascular approach using an electrolytic detachable platinum coil [U.S. RE42756, to GUGLIELMI et al, entitled Endovascular electrolytically detachable wire and tip for the formation of thrombus in arteries, veins, aneurysms, vascular malformations and arteriovenous fistulas]. In this procedure, one or more coils are introduced under radiologic guidance directly into the aneurysm via a microcatheter. The first coil is introduced into the aneurysm dome to form a basket, with subsequent coils of decreasing size placed within the aneurysm. The coils fill the aneurysm, blocking blood flow. A low positive direct electric current is then delivered to the guide wire. Thrombosis occurs within the aneurysm due to the attraction of negatively charged white blood cells, red blood cells, platelets and fibrinogen to the positively charged platinum coil within the aneurysm. Electrical current detaches the platinum coil within a few minutes due to electrolysis of the stainless steel wire closest to the thrombus-covered coil. The coiling may also be performed in conjunction with the use of a stent or balloon. For example, a wide-neck saccular aneurysm has a neck width of at least 4 mm, or a neck at least twice as wide as the height of the aneurysm dome, and it may be difficult for the coils to remain in such an aneurysm without the use of a stent. Recanalization of an aneurysm occurs when a previously treated aneurysm refills with blood. Recent studies indicate that recanalization occurs in more than 20% of coiled unruptured aneurysms and in more than 40% of coiled ruptured aneurysms. Consequently, many of these patients require re-coiling or open clip ligation [Brad SEIBERT, Ramachandra P. Tummala, Ricky Chow, Alireza Faridar, Seyed A. Mousavi and Afshin A. Divani. Intracranial aneurysms: review of current treatment options and outcomes. Frontiers in Neurology 2 (45, July 2011), doi: 10.3389/fneur.2011.00045, pp. 1-11; I. Y. L. TAN, R. F. Agid, and R. A. Willinsky. Recanalization rates after endovascular coil embolization in a cohort of matched ruptured and unruptured cerebral aneurysms. Interv Neuroradiol. 17 (1, 2011): 27-35].
More recently, the treatment of aneurysms has also been performed using stent devices that promote aneurysm thrombosis by diversion of flow through the parent vessel's lumen. The rationale of flow diversion is to treat the diseased vessel segment near the aneurysm, instead of directly treating the aneurysm itself. The parent artery adapts to the disruption of blood flow, leading to natural thrombosis by stasis within an aneurysm. The thrombosis is later reabsorbed while the artery is sealed in the presence of the flow diversion device. Sometimes, however, instead of remodeling the parent vessels and aneurysms, thrombus-associated autolysis of the aneurysm wall may also result in delayed rupture. Flow diversion devices are currently approved for treating unruptured large and giant aneurysms from the internal carotid artery between the superior hypophyseal and cavernous segments. Even so, it is thought that flow diversion can also be used in treating ruptured aneurysms, posterior circulation aneurysms, and distal anterior circulation aneurysms [Pietro I. D'URSO, Giuseppe Lanzino, Harry J. Cloft and David F. Kallmes. Flow Diversion for Intracranial Aneurysms: A Review. Stroke 42(2011):2363-2368; Adam M. BROUILLARD, Xingwen Sun, Adnan H. Siddiqui, Ning Lin. The use of flow diversion for the treatment of intracranial aneurysms: expansion of indications. Cureus 8(1): e472. DOI 10.7759/cureus.472. pp. 1-8; KULCSAR Z, Houdart E, Bonafé A et al. Intra-aneurysmal thrombosis as a possible cause of delayed aneurysm rupture after flow-diversion treatment. AJNR Am J Neuroradiol. 32 (1, 2011): 20-25].
Aneurysms that are associated with arteriovenous malformations (AVMs) are special in that they might be treated by stereotactic radiosurgery (SRS), incidental to radiological treatment of the AVM itself. An AVM is a tangle of blood vessels in the brain, or on the brain's surface, that bypasses normal brain tissue and diverts blood directly from the arteries to the veins without the presence of a capillary bed. AVMs can occur anywhere within the brain, are relatively uncommon (<1% of the population, more commonly in males than females) and are usually congenital. Aneurysms are associated with AVMs in approximately 8.5% of patients with AVMs [Michael T. LAWTON, W. Caleb Rutledge, Helen Kim, et al. Brain arteriovenous malformations. Nature Reviews Disease Primers 1, Article number: 15008 (2015) doi:10.1038/nrdp.2015.8, pp. 1-20; Esther J. KIM, Sandra Vermeulen, Francisco J. Li, David W. Newell. A review of cerebral arteriovenous malformations and treatment with stereotactic radiosurgery. Transl Cancer Res 3 (4, 2014): 399-410]. If the AVM is not too large and is in a location of the brain that is difficult to reach by conventional surgery, its treatment with SRS may be indicated. In this procedure, angiography, computed tomography, and/or magnetic resonance imaging is first performed to localize the AVM. Then, stereotaxis is used to focus ionizing radiation from collimated beams onto the AVM to produce direct damage to its vessels. Traditionally, the stereotactic procedure uses a set of three coordinates and a mechanical device with head-holding clamps and bars, in order to put the patient's head in a fixed position in reference to the coordinate system. The objective is to point the beam(s) of radiation precisely inside the brain, at calculated coordinates for the AVM. The underlying mechanism of action for radiosurgery is thought to be the induction of neointimal thickening of the abnormal vasculature, which leads to progressive narrowing and eventual vessel occlusion [CHANG S D, Shuster D L, Steinberg G K, Levy R P, Frankel K: Stereotactic radiosurgery of arteriovenous malformations: Pathologic changes in resected tissue. Clin Neuropathol 16(1997):111-116].
Three types of radiosurgical devices have been used for SRS—the Gamma Knife stereotactic radiosurgery apparatus (Elekta, Sweden); Linear Accelerator (LINAC) devices such as the CYBERKNIFE® (Accuray, Sunnyvale, Calif.), NOVALIS Tx™ (BrainLab, Germany), XKNIFE™ (Integra, New Jersey), and AXESSE™ (Elekta, Sweden) stereotactic radiosurgery apparatus, (among others); and proton beam devices. The Gamma Knife stereotactic radiosurgery apparatus uses multiple, simultaneous beams of gamma rays (from the radioactive decay of Cobalt-60) that converge at a fixed point after the patient has been positioned using a special couch, namely, the point in the patient's brain that is being treated. The original Gamma Knife devices used hemispherically arranged beams. The LINAC devices use a single X-ray beam that is produced by accelerating electrons onto a metal target. The X-ray beam is directed towards the patient from multiple sequential directions, so the underlying principle is the same as that of the Gamma Knife devices, except that the beams are applied sequentially rather than simultaneously. The term “beam” is defined here, as in Taber's medical dictionary, to be “Photons, atomic particles, or sound waves aligned in parallel rays.” According to this definition, a single photon or atomic particle cannot constitute a “beam” because the term refers to the substantially parallel alignment of multiple rays with respect one another. Also, a point source that emits photons or atomic particles in all directions cannot produce a beam of radiation (because omnidirectional rays are inherently not parallel with one another), unless the point source is accompanied by a waveguide or collimation-aperture device that minimizes ray divergence or eliminates rays of radiation that are not aligned substantially parallel to one another. A stereotactic head frame may also be used with the LINAC device, but newer techniques use robotics (e.g., industrial robotic arm used in the CYBERKNIFE® stereotactic radiosurgery apparatus) in which real-time imaging is performed to track the location of the target tissue as treatment is performed, thereby eliminating the need for a stereotactic head frame. The term “stereotactic radiosurgery” is used herein to include the use of methods for which a stereotactic head frame is not needed, because the targeting method is still based on stereotaxy. In addition to stereotactic radiosurgical devices that use gamma or X-rays, there also exist devices that irradiate the patient with charged particles (ordinarily protons, but could also be 1H, 4He, 12C, or 16O) [Timothy D. SOLBERG, Robert L. Siddon, and Brian Kavanagh. Historical Development of Stereotactic Ablative Radiotherapy. pp. 9-35 In: S. S. Lo et al. (eds.), Stereotactic Body Radiation Therapy, Medical Radiology. Berlin and Heidelberg: Springer-Verlag, 2012].
For the less than 10% of AVMs that have an associated aneurysm, stereotactic radiosurgery should not be considered to be a treatment of the aneurysm per se. This is because the whole AVM is irradiated, preferably with doses of 16 to 25 Gy at the margins of the AVM, with a sharp dose fall-off outside the treatment volume. According to LUNSFORD and his colleagues, if an aneurysm is located within the central part of the AVM (within the nidus, or location of the vessel tangle), the objective is to assure that the procedure does not cause a hemorrhage, rather than specifically to obliterate the aneurysm. If the aneurysm is located immediately proximal to the AVM (in the sense of blood flowing by the aneurysm and into the AVM), LUNSFORD says that the aneurysm will likely close as the AVM is obliterated, although that is not the primary objective of the stereotactic radiosurgery. However, if the aneurysm is located more than one arterial branch division proximal to the AVM, the aneurysm should be treated by itself, either before or immediately after the AVM stereotactic radiosurgery, using clipping or endovascular embolization [L. Dade LUNSFORD, Ajay Niranjan, Douglas Kondziolka, Sait Sirin and J. C. Flickinger. Arteriovenous Malformation Radiosurgery: A Twenty Year Perspective. Clinical Neurosurgery 55(2008):108-119].
The present invention discloses that the treatment of an unruptured aneurysm that is not associated with an arteriovenous malformation can also be performed using a focused beam of ionizing radiation that is delivered to the brain of a patient, i.e., using SRS. The inventor is unaware of stereotactic radiosurgery having ever been used to treat a non-AVM-associated, unruptured aneurysm, even though stereotactic radiosurgery of the brain has been practiced routinely for over 50 years. In fact, as described below, it appears that there have been only two reported instances in which stereotactic radiosurgery might have been used successfully to treat even a ruptured, non-AVM-associated aneurysm, 15 cases in which such patients died shortly after SRS treatment of their ruptured aneurysm, and one case in which the outcome is unknown.
According to NIRANJAN and colleagues, a 61 year old woman had sustained a hemorrhage from an aneurysm. One of the early pioneers of stereotactic radiosurgery (Leskell) “insisted to try” stereotactic radiosurgery on her aneurysm. That stereotactic radiosurgery was evidently against the advice of his colleagues, otherwise NIRANJAN would not have used the term “insisted.” Perhaps Leskell wanted to try using SRS because the patient is said to have refused conventional surgery to deal with the hemorrhaged aneurysm. The treatment apparently occurred before 1983, because in a historical account dated 1983, Leskell's group had already tried to treat five cases of arterial aneurysm (see below the work of Forster). Leskell did not publish details of the case anywhere, but angiograms documenting the woman's aneurysm appear in a 1985 book chapter by STEINER on the subject of treating AVMs, within a discussion of the mechanism of radiosurgical treatment of AVMs. STEINER notes that the woman had a “spasm of [the] posterior communicating and posterior cerebral arteries” and “was stuporous for several weeks following the ischemic effects of vasospasm following a subarachnoid hemorrhage.” Because the spasm may have been considered by Leskell to be a risk factor for having another hemorrhage, that may have been another reason that Leskell decided to go ahead and treat the patient using SRS, rather than simply surveil the woman. At the time of the stereotactic radiosurgery, STEINER says that the spasm was not present, but clearly there was no guarantee that it would not return. In any event, after the stereotactic radiosurgery, the woman's aneurysm became progressively smaller over next 11 months, and it was eventually obliterated [A. NIRANJAN, L. D. Lunsford, J. C. Flickinger, J. Novotny, J. Bhatnager, and D. Kondziolka. Gamma Knife: Clinical Experience. Chapter 66 in: Textbook of Stereotactic and Functional Neurosurgery, Volume 1 (Andres M. Llano, Philip L. Gildenberg, and Ronald R. Tasker, eds.) Berlin: Springer, 2009. p. 1071; STEINER, L. Radiosurgery in cerebral arteriovenous malformations. In: Fein J M and Flamm E, editors. Cerebrovascular surgery, vol 4. New York: Springer-Verlag; 1985. pp. 1161-1215, at pp. 1209-1210; Lars LEKSELL. Stereotactic radiosurgery. Journal of Neurology, Neurosurgery, and Psychiatry 46(1983):797-803].
The woman's aneurysms had several unusual features that are apparent from her angiograms. First, the aneurysm was not located at the apex of a bifurcation where two small arteries branch from a larger one. Instead, it seems to be associated primarily with a single vessel. Second, as noted by NIRANJAN, “the posterior communicating artery adjacent to the aneurysm also progressively narrowed in caliber and ultimately was obliterated without a neurological deficit. The patient refused a vertebral angiography, so we cannot know whether the aneurysm would fill or not from posterior circulation.” Therefore, the obliteration of the aneurysm after 11 months may just has well be attributable to the disappearance of the vessel to which it was attached, rather than to radiation that was administered solely to the aneurysm. The disappearance of the whole vessel leads one to suspect that it was experiencing vasculitis, which would also account for a weakening of the vessel wall that could give rise to the aneurysm in the first place. This is in contrast to the etiology of most saccular aneurysms, which involves characteristic blood flow patterns in the vicinity of vessel bifurcations, in combination with maladaptive remodeling of the vessel wall in response to the resulting localized hemodynamic stresses. Although all aneurysms may exhibit inflammation to some extent, in an ordinary saccular aneurysm, one would not expect the inflammation to be so pronounced that it would be accompanied by a vanishing vessel that is apparently experiencing vasculitis. Another explanation for the disappearance of the vessel might be that there was excessive unintentional irradiation of the vessel itself, and the resulting damage to the vessel ultimately brought about its resorption, secondarily obliterating the aneurysm.
STEINER commented that “It needs to be emphasized that radiosurgery is an inadequate treatment for aneurysms that have recently bled, and it remains to be determined whether it has any place in the treatment of aneurysms that have not bled.” Evidently, Leskell's colleagues were at least willing to try stereotactic radiosurgery on more aneurysms that did not involve an AVM, and according to NIRANJAN, “an additional 15 cases of arterial aneurysms were treated by Forster at [the] Karolinska Institute. All except one died of a hemorrhage a few weeks to months after the Gamma Knife treatment.” Apparently, those additional 15 cases were never described in any publication, presumably because Forster was not inclined to publish negative results. So, we have no way of knowing anything specific about the 15 cases, or what was different about the one patient who did not die soon after treatment. We can only infer that the negative experience concerning the radiosurgical treatment of ruptured aneurysms was communicated by word-of-mouth among all the practitioners of stereotactic radiosurgery at that time, who as of 1985 were developing stereotactic radiosurgery at only a very small number of sites around the world, primarily in Sweden [Lars LEKSELL. Stereotactic radiosurgery. Journal of Neurology, Neurosurgery, and Psychiatry 46(1983):797-803; Timothy D. SOLBERG, Robert L. Siddon, and Brian Kavanagh. Historical Development of Stereotactic Ablative Radiotherapy. pp. 9-35 In: S. S. Lo et al. (eds.), Stereotactic Body Radiation Therapy, Medical Radiology. Berlin and Heidelberg: Springer-Verlag, 2012].
The only other report of stereotactic radiosurgery being used to treat an aneurysm not associated with an AVM is also one in which a hemorrhage had already occurred. The aneurysm was not a saccular aneurysm, but was instead a Charcot-Bouchard aneurysm, i.e., one associated with a distal lenticulostriate artery. Again in this case, the patient had refused surgery to deal with the hemorrhaged aneurysm, so as a last resort, the physicians tried stereotactic radiosurgical treatment with a Gamma Knife. The patient recovered, and after 22 months, the aneurysm was found to have been obliterated. In their report of the case, the radiosurgeons state that the “excellent recovery is probably not the direct effect of the GKS [Gamma Knife Surgery] treatment because the treatment was done to prevent bleeding. How the patient recovered from the initial bleeding is still somewhat unknown and is a separate issue. From a single case, it is impossible to determine if GKS made the aneurysm disappear or if it resolved spontaneously. In other words, this is an anecdotal case so it cannot imply that there is necessarily cause and effect here” [LAN Z, Li J, You C, Chen J. Successful use of Gamma Knife surgery in a distal lenticulostriate artery aneurysm intervention. Br J Neurosurg 26 (1, 2012): 89-90]. Occasionally, aneurysms do in fact thrombose and obliterate spontaneously, and LAN's reservations concerning cause and effect applies not only to that case, but also to the above-mentioned case of the 61 year old woman [CHOI C-Y, Han S-R, Yee G-T, Lee C-H. Spontaneous regression of an unruptured and non-giant intracranial aneurysm. Journal of Korean Neurosurgical Society. 52 (3, 2012): 243-245; JAYAKUMAR P N, Ravishankar S, Balasubramaya K S, Chavan R, Goyal G. Disappearing saccular intracranial aneurysms: do they really disappear? Interventional Neuroradiology 13 (3, 2007): 247-254].
The present invention discloses that stereotactic radiosurgery can be used to treat unruptured saccular aneurysms that are not associated with an AVM. Despite the undisputed need for the treatment of at least some unruptured saccular aneurysms that are not associated with an AVM, nobody has ever reported having tried using stereotactic radiosurgery on such an aneurysm, even though the stereotactic radiosurgery of brain structures has become routine over the last 50 years. This is possibly due to the early negative experience involving 15 patients that was recounted above with regard to the radiosurgical treatment of ruptured aneurysms, as well as to the equivocal and anecdotal success that was reported in only two cases of ruptured aneurysms the 61 year old woman and the patient with an aneurysm associated with a lenticulostriate artery. The only other instance in which ionizing radiation has been used to treat an aneurysm involved brachytherapy with 32P (not gamma or X irradiation), in animal experiments that showed recanalization of thrombus after coil occlusion in experimental models can be inhibited by in situ beta radiation using 32P ion-implanted platinum coils [RAYMOND J, Mounayer C, Salazkin I, Metcalfe A, Gevry G, Janicki C, Roorda S, Leblanc P. Safety and effectiveness of radioactive coil embolization of aneurysms: effects of radiation on recanalization, clot organization, neointima formation, and surrounding nerves in experimental models. Stroke 37(8, 2006):2147-2152]. The present invention is fundamentally different from that 32P brachytherapy, because the work of RAYMOND and colleagues involved endovascular entry, whereas the present invention is noninvasive. According to the present disclosure and Taber's Medical Dictionary, noninvasive procedures are defined as follows. “Noninvasive procedures do not involve tools that break the skin or physically enter the body.” And because more than 50% of the beta particles emitted by 32P are absorbed within 1 mm of tissue, use of 32P is generally incapable of reaching all sites in the vessel wall, unlike the present invention, which can also selectively target particular portions of the aneurysm (e.g., only the aneurysm dome).
A motivation for the present disclosure is that the decision as to whether to treat the aneurysm with clipping or coiling or flow diversion, versus surveillance of the aneurysm, is based in part on the estimated risk of the surgery involving clipping or coiling or flow diversion. The complication rate related to treating small unruptured aneurysms using open surgery is reportedly approximately 4%. Because stereotactic radiosurgery avoids the risks associated with physically entering the patient, it potentially has less risk than the procedures in current use, e.g., by virtue of the fact that a craniotomy is not performed. Accordingly, aneurysms that would otherwise just be surveilled might instead be treated by the disclosed methods without increasing risk to the patient. For example, the presently disclosed methods contemplate that some smaller aneurysms that would otherwise be surveilled can justifiably be treated, thereby preventing a potential rupture. As another example, aneurysms at locations that are relatively difficult to reach by current surgical methods may instead be treated by radiosurgery. Thus, aneurysms of the posterior fossa are more difficult to clip than aneurysms of the anterior circulation, so the former aneurysm might be treated with stereotactic radiosurgery rather than clipping. Or because tortuous vessels may make it difficult to access some aneurysms endovascularly, or if the aneurysm is located at a site that is dangerously close to vital anatomic regions, or if the patient is unable to tolerate conventional operative intervention, the aneurysms may instead be treated by stereotactic radiosurgery.
A second motivation for the present disclosure is the inventor's recognition that the objective of the stereotactic radiosurgery need not be the obliteration of the aneurysm. The present objective is instead to impede the progression of the aneurysms towards rupture. Thus, if the aneurysm is obliterated by the stereotactic radiosurgery, then the progression towards rupture is inherently retarded. But if the stereotactic radiosurgery causes the aneurysm to be maintained in an innocuous state without obliteration, then the invention's objective is also satisfied. And if an aneurysm is obliterated by the procedure, a further objective of the invention is to prevent or delay the recurrence of an aneurysm at that site.
Finally, the use of stereotactic radiosurgery and coil embolization should be regarded as potentially complementary, rather than mutually exclusive for treating an unruptured aneurysm. The present invention may use radiosurgery to target the lumen of coil-embolized intracranial aneurysms to facilitate thrombosis and scarring for aneurysm occlusion and to reduce the incidence of recanalization. The present invention may also use radiosurgery to target the lumen of coil-embolized intracranial aneurysms that have demonstrated recurrence, to promote thrombosis and scarring for re-occlusion.
It should also be noted that the use of stereotactic radiosurgery to treat an unruptured saccular aneurysm is counterintuitive, considering what is presently known about the mechanisms of aneurysm growth and rupture. Hemodynamic analysis indicates that flow-induced wall shear stress plays a fundamental role in the growth of aneurysms. The response to that stress is myointimal hyperplasia, whereby an arterial wall responds not only to hemodynamic stress, but also to other forms of injury as well, in a process collectively known as vascular remodeling [Gary H. GIBBONS, and Victor J. Dzau. The Emerging Concept of Vascular Remodeling. N Engl J Med 330(1994):1431-1438; HERITY N A, Ward M R, Lo S, Yeung A C. Review: Clinical aspects of vascular remodeling. J Cardiovasc Electrophysiol. 10 (7, 1999): 1016-1024]. In myointimal hyperplasia, proliferation and migration of vascular smooth muscle cells lead to formation of a thickened fibroid layer on the luminal surface of the vessel. The resulting thickening of the wall will alter the geometry of the aneurysm, which in turn will alter the hemodynamics of the flow of blood into and out of the aneurysm, which will in turn alter (and possibly increase) the wall shear stress, leading to an interplay that causes to aneurysm to dynamically change its structure. During the hyperplasia, the vascular smooth muscle cells that migrate from the vascular wall to the luminal surface secrete matrix metalloproteinases that destroy parts of the wall matrix and make the migration of smooth muscle cells possible. But if the destruction of the vessel wall, aided by any inflammatory response, weakens the wall more than the hyperplasia thickens and strengthens the wall, rupture will eventually occur when the wall stress exceeds the wall strength. It is not readily apparent why deliberately causing additional injury to the aneurysm wall using ionizing radiation would not actually promote rupture of the aneurysm, instead of impeding progression of the aneurysm towards rupture. Furthermore, radiotherapy (including whole brain exposure and brachytherapy), is known to have produced aneurysms that did not exist before the radiotherapy [NANNEY A D 3rd, El Tecle N E, El Ahmadieh T Y, Daou M R, Bit Ivan E N, Marymont M H, Batjer H H, Bendok B R. Intracranial aneurysms in previously irradiated fields: literature review and case report. World Neurosurg 81 (3-4, 2014): 511-519].